multicatalytic processes based on supported ionic liquid-like … · some of them show evidence of...
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Multicatalytic processes based on SILLPs S.V. Luis
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Multicatalytic processes based on Supported Ionic Liquid-Like Phases (SILLPs)
S.V. Luis B. Altava, M.I. Burguete, E. García-
Verdugo, E. Peris, R. Porcar Sustainable and Supramolecular
Chemistry Group University Jaume I
Castellón, Spain www.quimicasostenible.uji.es
Multicatalytic processes based on SILLPs S.V. Luis
XXI CENTURY: THE SEARCH FOR SUSTAINABILITY
27/05/2014 S. Luis 2
Multicatalytic processes based on SILLPs S.V. Luis
XXI CENTURY: THE SEARCH FOR SUSTAINABILITY
27/05/2014 S. Luis 3
Methods
Substrates
Added-value
Products
Multicatalytic processes based on SILLPs S.V. Luis
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Green Chemistry
Toolbox
Tools
Catalysis Heterogeneous catalysis
Alternative Solvents
Microwave heating
Flow Process
Multicatalytic processes based on SILLPs S.V. Luis
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It is possible to design ionic liquids of suitable properties
by combining appropriate anions, cations, and varying
their structure
Why ILs?
N.V. Plechkova, K.R. Seddon Chem Soc Rev, 37 (1) (2008), pp. 123–150
Multicatalytic processes based on SILLPs S.V. Luis
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….Nobody is perfect!!
Multicatalytic processes based on SILLPs S.V. Luis
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Biphasic liquid-liquid systems:
require relatively large amounts of IL.
relatively expensive
some of them show evidence of low
biodegradability and high (eco)toxicological
properties.
require an extraction solvent
The immobilisation of ILs onto a support or structured
material (e.g. by simple impregnation, covalent linking
of the cation, sol-gel method, etc):
SILLP: Supported Ionic Liquid-Like Phases IL
Ionic liquids as “Green Solvents”
Multicatalytic processes based on SILLPs S.V. Luis
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Ionic liquids as “Green Solvents”: SILLPs
SILLPs: Immobilisation of ILs onto a support or structured materials
(by covalent linking of the cation) to transfer the properties of the IL to an
inert support
minimize the amount of ILs used: lower cost
easy separation and recyclability
potential for the development of continuous processes
solventless reactions or in SCFs
N
N
R
N
N
R
N
NR
N
N
R
N
NR
Cl
Cl Cl Cl
Cl
Cat
Cat
Cat
Substrates Products
Flow Flow
SCF SCF
E-1
S P
Multicatalytic processes based on SILLPs S.V. Luis
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Monomers or monomeric-ILs
or
Films
Beads
Rods
Membrane
Polymerization/modification
Soluble materials
Polymerization/modification
+
+
Crosslinking insoluble materials
100 m
Polymeric Ionic Liquids (PILs)
FilmsElectrospinning
NPs-PILs solutions
PILS SILLPS
Ionic liquids as “Green Solvents”: SILLPs
Multicatalytic processes based on SILLPs S.V. Luis
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Transfer the properties of the IL to an inert support
What properties?
modular
thermal stability
polarity
Mw heating
ability to stabilise different catalysts
ILs vs. SILLPs:
How much do they look alike?
Multicatalytic processes based on SILLPs S.V. Luis
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Cl
The length of the chain in the IL allows to modulate
the polarity
* Hydrophylicity: -Me > -Bu > -De
macro-PS-DVB 1.2 mmol Cl/g
N
NCH3
Cl N
NC4H9
Cl
N
NC10H21
Cl
Properties of SILLPs:
Polarity/Behaviour in water
Multicatalytic processes based on SILLPs S.V. Luis
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Synthesis of Supported Ionic Liquid-Like Phases:
SILLPs
TGA
-80
-60
-40
-20
0
20
40
60
80
TfO - NTf
2
-
BF 4
-
SbF 6
-
Cl -
D T
Anion 1.2 meq. / g. 2.2 meq. / g. 4.3 meq. / g.
Chem. Eur. J., 2011
Multicatalytic processes based on SILLPs S.V. Luis
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Pyrene as solvatochromic fluorescent probe
The pyrene solvent polarity scale is defined as
the II/IIII emission intensity ratio
II/IIII increases with increasing solvent polarity
Hexane
0.61
Toluene
1.11
MeOH
1.33
CH3CN
1.75
DMF
1.82
- +
II/IIII
Properties of SILLPs: Polarity
Chem. Eur. J., 2011
1.15 1.29 1.40 1.64 0.93
N
N
Cl
N
N
NTf2
N
N
BF4
N
N
SbF6
Cl
Multicatalytic processes based on SILLPs S.V. Luis
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Rose Bengal
O
OII
O2C
Cl
ClCl
ClI
ONa
I
N
N
R
X
N NR
x2
x1
Photocatalysts
Organometalic and
metalic catalysts
Organocatalysts
MeNPs
Biocatalysts
Supported Ionic Liquid-Like Phases (SILLPs)
Multicatalytic processes based on SILLPs S.V. Luis
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Multicatalytic processes based on SILLPs S.V. Luis
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Benchmark Reaction: Heck reaction
Monolithic microreactor:
IL-DVB 40:60
2,1 meq IL/g
0,21 meq Pd(0)/g
0
20
40
60
80
100
120
20 40 60 81 101 121 141 Cycles (bed vol.)
%
0
50
100
150
200
250
300
TO
N
Yield
TON
• 100% trans
• high stability 420min (7h)
• TON/cycle: 2.28
• Residence time: 2.98min
scEtOH
(Tc=241oC, Pc=61 bar)
J. Catal., 2010
Application of SILLPs: Catalytic supported PdNPs
I
Cat
+CO2MeCO2Me
• T>150oC
• T>250oC transesterification.
Multicatalytic processes based on SILLPs S.V. Luis
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Entry Cycle Yield (%)
TOF50 (h-1)
1 2 99 2727
2 8 99 2970
HPLC chromatograms
Salt containing Salt free
Under continuous flow with scCO2:
Salt free, solvent free
Adv. Synth. Catal., 2010
Application of SILLPs: Catalytic supported PdNPs
Polymeric cocktail
Multicatalytic processes based on SILLPs S.V. Luis
Biocatalytic continuous biodiesel
synthesis in scCO2
The presence of t-butanol as
cosolvent avoids poisoning of
the biocatalyst by the side
product glycerol
18
Application of SILLPs: Supported biocatalysts
ChemSusChem 2012
Multicatalytic processes based on SILLPs S.V. Luis
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Why?
Reaction induced by light.
Clean and selective processes.
How?
adsorbing Rose of Bengal.
N
N
CH3
Cl-
MeOH/ Tambiente /48h
RB-COONaRB-COO-
N
N
CH3
NaCl
N
N
CH3Cl-
450 500 550 600
0,0
0,2
0,4
0,6
0,8
1,0
Abs
Longitude de onda (nm)
0 min
60 min
120 min
180 min
240 min
RB =
Application of SILLPs: Supported photocatalysts
Multicatalytic processes based on SILLPs S.V. Luis
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0.1 mL/min
0.1 mL/min
0.05 mL/min Fluidized bed reactor
10 mL
250 mg RB-SILLP
Application of SILLPs: Supported photocatalysts
Multicatalytic processes based on SILLPs S.V. Luis
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Cyanosilylation of Carbonyl Compounds
BF4 SbF6 NTf2 TfO Cl
0
20
40
60
80
100
120
Re
lative
Re
action r
ate
0 50 100 150 200 250 300 350 400 450 500
0
10
20
30
40
50
60
70
80
90
100
Time (minutes)
Yie
ld (
%)
BF4 SbF6 NTf2 TfO Cl
NN R
R'X
Functionalisation Degree
Type of substitution
Polymer Type
Counterion
More basic SILLP more active catalyst > 99% yield for different
ketones and aldehydes
Green Chem., 2014, 16, 1639.
Multicatalytic processes based on SILLPs S.V. Luis
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Cyanosilylation of Carbonyl Compounds
Green Chem., 2014
Fix –bed
reactor
ATR-FTIR
pump
0 10 20 30 40 50 60 70 80 90 100 110 120
0,00
0,02
0,04
0,06
0,08
0,10
0,12
0,14
0,16
Ab
s. p
rod
uc
t (c
m-1)
time (min)
0,00
0,05
0,10
0,15
0,20
0,25
0,30
Ab
s. re
ac
tan
t (c
m-1)
0.1 mL/min 0.2 mL/min
0.3
mL/min
0.4
mL/min
0.5 mL/min
GC(Yield):36% GC(Yield):87% GC(Yield):95%
GC(Yield):
95%
GC(Yield):
93%
95% yield,
solvent-free,
excellent catalytic activity,
continuous monitoring
FLOW PROCESS
Multicatalytic processes based on SILLPs S.V. Luis
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Natural biosynthetic systems
many catalytic reactions occurring in the
same vessel
products from one step do not inhibit the next
one.
Reagents compatibility: oxidants/reductants
or nucleophile/electrophile together.
linear combination of irreversible steps
Cells produce complex compounds
Multicatalytic processes based on SILLPs S.V. Luis
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Non-natural biosynthetic systems
A + B C D E F
Isolation of incompatible catalysts
Reagent(s)/product(s) compatibility.
linear combination of irreversible steps
Multicatalytic processes based on SILLPs S.V. Luis
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Synthesis of cyanohydrin
Step 2: two reactions: hydrolysis of
TMSOR and acetylation
Step 3: Enzymatic trans-esterification,
enantiopure cyanohydrins
Overall: 4 reactions in 3 consecutive steps
Step 1 Step 2
Step 3
Multicatalytic processes based on SILLPs S.V. Luis
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Synthesis of cyanohydrin
1 Step 2 Step
Batch process:
3 Step
1 eq acetophenone
1,2 eq TMSCN; rt,
24h.
Cat: 25 mg/mmol
benzaldehyde
Yield: >99%
Step 1 Step 2
Step 3
1 eq substrate, 2 eq Ac2O, 40ºC,
24h.
50 mg cat / mmol substrate.
Yield: >99%
9,8 ml methyl-THF, 0,15ml n-propanol and
100 mg CAL-B (Novozyme 435) /mmol
substrate; 60ºC, 24h.
50% conv.,
ROH: 98% e.e., AcOR: 99% e.e.
Multicatalytic processes based on SILLPs S.V. Luis
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Synthesis of cyanohydrin
Batch process:
1 Step 2 Step
3 Step
One-pot multistep batch process
Multicatalytic processes based on SILLPs S.V. Luis
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Synthesis of cyanohydrin- Flow process
Step 1
Step 2
T = 25 oC, 500 mg cat
T = 50 oC
500 mg cat
1 eq. + 1.1 eq 95 % Yield
2 eq
0.01 mL/min
99 % Yield
0.019 mL/min
Up to 85 overall yield
for the two steps
Single pot reactor mixing catalyst
and reagents does not work
Stable for up to 12h continuous use
9 µL/min
0
20
40
60
80
100
3,5 5,7 6,2 8,9 11,7
Yie
ld (
%)
Multicatalytic processes based on SILLPs S.V. Luis
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0
20
40
60
80
100
4 5 6 6 7 8 21 22 24 27 28 30 45 47 47 49 51 53 54 55 56 57 70
Yie
ld (%
)
Time (hours)
62 % Yield
92 % Yield
Synthesis of cyanohydrin- Flow process
1.5 equiv 2 equiv
Multicatalytic processes based on SILLPs S.V. Luis
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Synthesis of cyanohydrin- Flow process
Step 3 T = 65 oC
100 mg cat
0.35 mL/min Me-THF:IPA,
0.1 M AcOR
0
20
40
60
80
100
20 35 50 65 70
Time (min)
Yie
ld (
%)
Up to 48 % conversion
99% e.e. ROH
95% e.e. AcOR
Multicatalytic processes based on SILLPs S.V. Luis
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R-I
R-II pump-1
pump-2 pump-3
R-III (CALB)
2 equiv.
1 + 1.2 equiv.
Synthesis of cyanohydrin- Flow process
Multicatalytic processes based on SILLPs S.V. Luis
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Synthesis of cyanohydrin- Flow process
Four consecutive reactions
Three synthetic steps “one-pot”
Metal free synthesis
Five days ToS highly stable.
Final product in high yield
> 98%ee for the (R) acetylated product
R-I
R-II pump-1
pump-2 pump-3
R-III (CALB)
2 equiv.
1 + 1.2 equiv.
Multicatalytic processes based on SILLPs S.V. Luis
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Synthesis of amino alcohols
RCO2OH
H2O2
H2O
RCO2HR'OH +
RCO2R'
Cat-1
Cat-1
R-1
R-2
R-3(1)
O
(2)
Step-1
R''NH2
Cat-2O
(2)
Step-2
R-4
OH
NHR''(3)
Four consecutive reactions
Two synthetic steps “one-pot”
two (Bio)catalytic steps (enz. and chemo)
Potential transfer to flow conditions.
Epoxidation
Ring-opening of epoxide
Multicatalytic processes based on SILLPs S.V. Luis
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Synthesis of amino alcohols- Epoxidation
RCO2OH
H2O2
H2O
RCO2HR'OH +
RCO2R'
Cat-1
Cat-1
R-1
R-2
R-3(1)
O
(2)
Step-1
Step 1: lipase‐mediated epoxidation of cyclohexene
DMC as solvent and source of peroxy acids (residues CO2 and MeOH)
Multicatalytic processes based on SILLPs S.V. Luis
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Synthesis of amino alcohols-
Flow Epoxidation
RCO2OH
H2O2
H2O
RCO2HR'OH +
RCO2R'
Cat-1
Cat-1
R-1
R-2
R-3(1)
O
(2)
Step-1
Stable catalyst for
hydroperoxydation
Multicatalytic processes based on SILLPs S.V. Luis
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Synthesis of amino alcohols-
Flow Epoxidation
RCO2OH
H2O2
H2O
RCO2HR'OH +
RCO2R'
Cat-1
Cat-1
R-1
R-2
R-3(1)
O
(2)
Step-1
cyclohexene (1equiv.), H2O2 (50%) (2.5
equiv.), dimethyl carbonate (0.1 mmol/mL),
1/8 TFA fix-bed reactor (180 mg),
45 ºC , 5µL/min, 97% of yield was obtained.
same conditions but 1 equiv. of H2O2 (50%),
72% of yield was obtained.
Epoxidation feasible with CALB as catalyst for hydroperoxydation
Multicatalytic processes based on SILLPs S.V. Luis
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Synthesis of amino alcohols-
Epoxide opening- Flow process
R''NH2
Cat-2O
(2)
Step-2
R-4
OH
NHR''(3)
cyclohexene epoxide (1equiv)
aniline (1equiv) in dimethyl
carbonate (0.25 mmol/mL)
(flow of 7µL/min),
TFA reactor packed with
SILLP-SO3-Sc (264 mg),
at 45 ºC.
99% of yield was obtained.
Multicatalytic processes based on SILLPs S.V. Luis
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Synthesis of amino alcohols-
Epoxide opening- Flow process
R''NH2
Cat-2O
(2)
Step-2
R-4
OH
NHR''(3)
0
10
20
30
40
50
60
70
80
90
100
15 h 24 h 39 h 49 h 63 h 66 h 70 h 97 h
yield (%) cyclohexene epoxide (1equiv)
aniline (1equiv) in dimethyl
carbonate (0.25 mmol/mL)
(flow of 10µL/min),
SILLP-SO3-Sc (1g),
at 45 ºC.
99% of yield was obtained.
Stable for 97 hours of
continuous use
Multicatalytic processes based on SILLPs S.V. Luis
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Synthesis of amino alcohols-
Coupled flow process
Step 1
Step 2
T = 45 oC
180 mg CALB-SILLP
T = 45 oC
265 mg cat
1 eq. + 1 eq 95 % Yield
0.1 mmol/mL
5µL/min
94 % Yield
0.25 mmol/mL
2µL/min
Up to 94 yield for step 2
Single-pot batch rector, mixing
catalyst and reagents does not
work (one pot two additions)
Multicatalytic processes based on SILLPs S.V. Luis
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Synthesis of amino alcohols
RCO2OH
H2O2
H2O
RCO2HR'OH +
RCO2R'
Cat-1
Cat-1
R-1
R-2
R-3(1)
O
(2)
Step-1
R''NH2
Cat-2O
(2)
Step-2
R-4
OH
NHR''(3)
Five consecutive reactions
Three synthetic steps “one-pot”
Three (Bio)catalytic steps (two enz. one chemo)
Possible to transfer to flow conditions.
Enantioselective production of amino alcohol
Multicatalytic processes based on SILLPs S.V. Luis
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Synthesis of amino alcohols-Resolution
Flow Process
Aminoalcohol (0.25 mmol/mL)
(flow of 7µL/min), Novozyme (264 mg),
at 50 ºC.
47% of yield was obtained.
93 % ee
99 % ee 47% yield
99% ee carbonate
Step 1: aminoalcohol (1 eq),
CAL-B (50 mg), dimethyl
carbonate (1 mL) for 71 h at 50 ºC
and 250 rpm.
Multicatalytic processes based on SILLPs S.V. Luis
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Synthesis of amino alcohols-Resolution
Flow Process
47 % conversion
99 % e.e. ester
97 % e.e. alcohol
Stable 27 hours continuous
use
Enantioselective production of
amino alcohol
0
20
40
60
80
100
0
20
40
60
80
100
5 10 15 20 25
yield
(%)
conv.
e.e.
Time on Stream (hour)
(%)
Multicatalytic processes based on SILLPs S.V. Luis
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Synthesis of amino alcohols
Flow Process Step 1
Step 2
T = 45 oC
180 mg CALB-SILLP
T = 45 oC
265 mg cat
1 eq. + 1 eq
95 % yield
0.1 mmol/mL
5µL/min
94 % yield
0.25 mmol/mL
2µL/min
T = 50 oC
500 mg Novozyme 435
3 Step 47% yield, 99% ee carbonate
Five consecutive reactions
Three synthetic steps “one-pot”
Three (Bio)catalytic steps (two enz. one chemo)
Enantioselective production of amino alcohol
Multicatalytic processes based on SILLPs S.V. Luis
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It is possible the immobilisation of ILs onto a support by covalent linking,
transferring the IL properties to the solid phase leading to i.e. monolithic or gel-
type polymer supported ionic liquid phases (SILLPs) minimize the amount of ILs used
avoid toxicological concerns
easy separation and recyclability
mini-flow catalytic reactors for continuous processes in SCFs/green solvents
can be applied to both Chemical Catalysis and Biocatalysis
many potential applications beyond
Conclusion
Cat
A + B C D E F
Multicatalytic processes based on SILLPs S.V. Luis
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Acknowledgements
Dr. Eduardo García-Verdugo
Dr. M. Isabel Burguete
Dr. Belen Altava Dr. Maia Sokolova
Dr. Amrit Puzari
Dr. Naima Karbass
Dr. Victor Sans
Dr. Julian Restrepo
Dr.R. Porcar Dr. D. Izquierdo
S. Marti
S. Montoliu
M. Maciá,
E. Perís
D. Nuevo AND Hanno and Fabien and Milena, Ivan….
Funding:
- Spanish Education and Resarch
Department (Plan Nacional de I+D)
- Generalitat Valenciana
Dr. P. Lozano
University of Murcia